Identification of the pathogenesis of nephrotic syndrome by analyses of signal transduction and proteome

2012 Fiscal Year Final Research Report

• Project/Area Number: 22390204
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: 独立行政法人国立成育医療研究センター (2012); The University of Tokyo (2010-2011)
• Principal Investigator: IGARASHI Takashi 独立行政法人国立成育医療研究センター, 総長 (70151256)
• Co-Investigator(Kenkyū-buntansha): HATTORI Seisuke 北里大学, 薬学部, 教授 (50143508) ; HARITA Yutaka 東京大学, 医学部付属病院, 講師 (10451866)
• Project Period (FY): 2010 – 2012
• Keywords: 小児腎 / 泌尿器学

Research Abstract

Slit diaphragm, an intercellular junction between renal glomerular epithelial cells (podocytes), is essential for the permselectivity in glomerular ultrafiltarion. To establish specific therapy for pediatric nephrotic syndrome, we focused on the structure and function of slit diaphragm (SD) and investigated the pathogenic mechanism of proteinuria and nephrotic syndrome. We revealed (I) the importance of dynamics of slit diaphragm turnover in the maintenance of slit diaphragm, (II) the novel component of slit diaphragm, (III) the mechanism of intracellular calcium concentration by slit diaphragm signaling, and (IV) the changes of expression of functional proteins in podocytes of nephrotic patients. Our data provide new molecular insights into the formation and maintenance of SD and its dysfunction in hereditary and idiopathic nephrotic syndrome.

Research Products

• [Journal Article] Tyrosine kinase signaling in kidney glomerular podocytes. (2011)
  • Author(s): Hattori S, Kanda S, Harita Y
  • Journal Title: Signal Transduct Volume: 2011 Pages: 31785
• [Journal Article] Tyrosine phosphorylation-dependent activation of TRPC6 regulated by PLC_<-γ>1 and nephrin: effect of mutations associated with focal segmental glomerulosclerosis. (2011)
  • Author(s): Kanda S, Harita Y, Shibagaki Y, Sekine T, Igarashi T, Inoue T, Hattori S
  • Journal Title: Mol Biol Cell Volume: 22 Pages: 1824-351
• [Journal Article] Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. (2011)
  • Author(s): Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C, Higashida M, Mikasa H, Nakaya Y, Takanashi S, Igarashi T, Kitagawa T, Sata M
  • Journal Title: Am Coll Cardiol Volume: 58 Pages: 248-255
• [Journal Article] A synthetic prostacyclin agonist, ONO-1301, ameliorates ventricular remodeling after acute myocardial infarction via upregulation of HGF in rat. (2011)
  • Author(s): Hirata Y, Soekia T, Yamadaa H, Shiotac A, Shimabukuroc M, Sakaid Y, Nakayamae M, Matsumotoe K, Igarashi T, Sata M
  • Journal Title: Biomedicine & Aging Pathology Volume: 1 Pages: 90-96
• [Journal Article] Increased Akt-mTOR signaling in lung epithelium is associated with respiratory distress syndrome in mice. (2011)
  • Author(s): Ikeda H, Shiojima I, Oka T, Yoshida M, Maemura K, Walsh K, Igarashi T, Komuro I
  • Journal Title: Mol Cell Biol Volume: 31 Pages: 1054-1065
• [Journal Article] Congenital infection-like syndrome with intaracranial calcification. (2011)
  • Author(s): Mizuno Y, Takahashi K, Igarashi T, Saito M, Mizuguchi M
  • Journal Title: Brain & Develop Volume: 33 Pages: 530-533
• [Journal Article] Model combining hydrodynamics and fractal theory for analysis of in vivo peropheral pulmonary and systemic resistance of shunt cardiac defects. (2011)
  • Author(s): Nakamura Y, Awa S, Kato H, Ito YM, Kamiya A, Igarashi T
  • Journal Title: J Theoret Biology Volume: 287 Pages: 64-73
• [Journal Article] IDH1 and IDH2 mutations are rare in pediatric myeloid malignancies. (2011)
  • Author(s): Oki K, Takita J, Hiwatari M, Nishimura R, Sanada M, Okubo J, Adachi M, Sotomatsu M, Kikuchi A, Igarashi T, Hayashi Y, Ogawa S
  • Journal Title: Leukemia Volume: 25 Pages: 1-3
• [Journal Article] nterstitial deletion of 13q14.13-q32.3 presenting with Arima syndrome and bilateral retinoblastoma. (2011)
  • Author(s): Takahashi K, Oka A, Mizuguchi M, Saitoh M, Takita J, Sato A, Mimaki M, Kato M, Ogawa S, Igarashi T
  • Journal Title: Brain & Develop Volume: 33 Pages: 353-356
• [Journal Article] Aberrations of NEGR1 on 1p31 and MYEOV on 11q13 in neuroblastoma. (2011)
  • Author(s): Takita J, Chen Y, Sanada M, Adachi M, Ohki K, Nishimura R, Hanada R, Igarashi T, Hayashi Y, Ogawa S
  • Journal Title: Cancer Science Volume: 102 Pages: 1645-1650
• [Journal Article] VIP36 protein is a target of ectodomain shedding and regulates phagocytosis in macrophage Raw 264.7 cells. (2011)
  • Author(s): Shirakabe K, Hattori S, Seiki M, Koyasu S, Okada Y
  • Journal Title: J Biol Chem Volume: 286 Pages: 43154-43163
• [Journal Article] Identification of three new autoantibodies associated with systemic lupus erythematosus using two proteomic approaches. (2011)
  • Author(s): Katsumata Y, Kawaguchi Y, Baba S, Hattori S, Tahara K, Ito K, Iwasaki T, Yamaguchi N, Oyama M, Kozuka-Hata H, Hattori H, Nagata K, Yamanaka H, Hara M
  • Journal Title: Mol Cell Proteomics Volume: 10 Pages: M110.005330
• [Journal Article] Glomerular proteins related to slit diaphragm and matrix adhesion in the foot processes are highly tyrosine phosphorylated in the normal rat kidney. (2010)
  • Author(s): Zhang Y, Yoshida Y, Nameta M, Xu B, Taguchi I, Ikeda T, Fujinaka H, Mohamed SM, Tsukaguchi H, Harita Y, Yaoita E, Yamamoto T
  • Journal Title: Nephrol Dial Transplant Volume: 25 Pages: 1785-95
• [Journal Article] Renal manifestations, progression and pathological findings in patients with R702 mutations in MYH9. (2010)
  • Author(s): SekineT, Konno M, Sasaki S, Moritani Sm Miura T, Wong WS, Nishio H Nishiguchi T, Yoshinari M, Tsuchiya S, Matsuyama T, Kanegane H, Ida K, Miura K, Harita Y, Igarashi T, Hattori M, Horita S, Saito H, Kunishima S
  • Journal Title: Kidney Int. Volume: 8 Pages: 207-14
• [Journal Article] ASPP2 regulates epithelial cell polarity through the PAR complex. (2010)
  • Author(s): Cong W, Hirose T, Harita Y, Yamashita A, Mizuno K, Hirano H, Ohno S
  • Journal Title: Curr Biol. Volume: 20 Pages: 1408-14
• [Journal Article] SIRP-alpha-CD47 system functions as an intercellular signal in the renal glomerulus. (2010)
  • Author(s): Kurihara H, Harita Y, Ichimura K, Hattori S, Sakai T
  • Journal Title: Am J Physiol Renal Physiol Volume: 299 Pages: F517-27
• [Journal Article] Four cases of postrenal renal failure induced by renal stone associated with rotavirus infection. (2010)
  • Author(s): Morita T, Ashida A, Fujieda A, Hayashi A, Meda A, Ohta K, Shimizu M, Sekine T, Igarashi T, Tamai H, Wakiguchi H
  • Journal Title: Clin Nephrol Volume: 73 Pages: 398-402
• [Journal Article] Case report: Prenatal intervention for severe anterior urethral valve. (2010)
  • Author(s): Mizuno Y, Tsuchida S, Kakiuchi S, Ishiguro A, Goishi K, Kamei Y, Kanamori Y, Yamazaki Y, Sekine T, Igarashi T
  • Journal Title: Pediatr Inter Volume: 52 Pages: e92-e95
• [Journal Article] Patients with Epstein-Fechtner syndrome owing to MYH9 R702 mutations develop progressive proteinuric renal disease. (2010)
  • Author(s): Sekine T, Konno M, Sasaki S, Moritani S, Miura T, Wong WS, Nishio H, Nishiguchi T, Ohuchi MY, Tsuchiya S, Matsuyama T, Kanegane H, Ida K, Miura K, Harita Y, Hattori M, Horita S, Igarashi T, Saito H, Kunishima S
  • Journal Title: Kidney Int Volume: 78 Pages: 207-214
• [Journal Article] Skin and subcutaneous blood flows of very low birth weight infants during the first 3 postnatal days. (2010)
  • Author(s): Ishiguro A, Sekine T, Kakiuchi S, Nishimura R, Goishi K, Tsuchida S, Ohtsu H, Igarashi T
  • Journal Title: J Matern Fetal Neonatal Med Volume: 23 Pages: 522-528
• [Journal Article] Four cases of postrenal renal failure induced by renal stone associated with rotavirus infection (2010)
  • Author(s): Morita T, Ashida A, Fujieda M, Hayash A, Maeda A, Ohta K, Shimizu M, Sekine T, Igarashi T, Tamai H, Wakiguchi H
  • Journal Title: Clinical Nephrol Volume: 73 Pages: 398-402
• [Journal Article] Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease. (2010)
  • Author(s): Sekine T, Konno M, Sasaki S, Moritani S, Miura T, Wong WS, Nishio H, Nishiguchi T, Ohuchi MY, Tsuchiya S, Matsuyama T, Kanegane H, Ida K, Miura K, Harita Y, Hattori M, Horita S, Igarashi T, Saito H, Kunishima S
  • Journal Title: Kidney Int Volume: 78 Pages: 207-214
• [Journal Article] Defective membrane expression of the Na+-HCO3- cotransporter NBCe1 is associated with familial migraine. (2010)
  • Author(s): Suzuki M, Paesschen WV, Stalmans I, Horita S, Yamada H, Bergmans BA, Legius E, Riant F, Jonghe PD, Li Y, Sekine T, Igarashi T, Fujimoto I, Mikoshiba K, Shimadzu M, Shohara M, Braverman N, Al-Gazali L, Fujita T, Seki J
  • Journal Title: Pnas Volume: 107 Pages: 15963-15968
• [Journal Article] Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling. (2010)
  • Author(s): Tasaki S, Nagasaki M, Kozuka-Hata H, Semba K, Gotoh N, Hattori S, Inoue J, Yamamoto T, Miyano S, Sugano S, Oyama M
  • Journal Title: PLoS One Volume: 5 Pages: e13926
• [Patent(Industrial Property Rights)] ポリペプチド (2010)
  • Inventor(s): 神田祥一郎、張田豊、服部成介、五十嵐隆、井上貴文
  • Industrial Property Rights Holder: 国立大学法人東京大学,学校法人北里研究所,学校法人早稲田大学
  • Industrial Property Number: 特願,2010-174155
  • Acquisition Date: 2010-08-03